The present invention relates to an efficient process for the preparation of the selective glucocorticoid receptor agents which are useful 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines.
The glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent anti-inflammatory agents. Steroidal GR ligands, however, have side effects associated with chronic dosing believed to be the result of cross-reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains. Therefore, nonsteroidal agents selective for GR are actively being researched for the treatment of inflammation, inflamatory disease, immune and autoimmune diseases.
The present invention is directed to an efficient process for the preparation of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines. In particular the present invention is directed to, 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline in an overall yield of 24% and with elimination of all column chromatography purification steps.
The present invention is directed to an improved seven-step process that eliminates column chromatography, improves throughput and increases the overall yield for the preparation of (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline. The improved seven-step process, described in Scheme 2 and more particularly in Examples 1-8, allows for the preparation of (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline on a larger scale than the processes reported in International Patent PublicationNumber WO 99/41256 and J. Med. Chem., 41 (1998) 303-310.
The process comprising treating 2-bromo-1,3-dimethoxybenzene, 2-iodo-1,3-dimethoxybenzene or 1,3-dimethoxybenzene with an organolithium reagent in a first solvent at a temperature of about xe2x88x925xc2x0 C. to about 15xc2x0 C., preferably about 0xc2x0 C. to about 5xc2x0 C., after complete addition of the organolithium reagent, the temperature is allowed to warm to ambient temperature and the reaction mixture is stirred for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0xc2x0 C. and then adding ZnCl2 while maintaining the temperature between xe2x88x925xc2x0 C. and 15xc2x0 C., preferably about xe2x88x925xc2x0 C. to about 5xc2x0 C., after complete addition of ZnCl2 allowing the temperature to warm to ambient temperature and allowing the reaction mixture to stir for about 1 to 4 hours, preferably about 2 hours, recooling the reaction mixture to about 0xc2x0 C. and adding methyl 2-bromo-5-nitrobenzoate, methyl 2-iodo-5-nitrobenzoate or methyl 5-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate followed by addition of first transition metal catalyst and maintaining the reaction temperature between about 10xc2x0 C. and about 55xc2x0 C., preferably between about 20xc2x0 C. and about 45xc2x0 C., about 30 minutes after complete addition of first transition metal catalyst adding isopropylacetate and stirring for about 20 to about 90 minutes and then filtering to provide methyl 2xe2x80x2,6xe2x80x2-dimethoxy-4-nitro-1,1xe2x80x2-biphenyl-2-carboxylate;
treating 2xe2x80x2,6xe2x80x2-dimethoxy-4-nitro-1,1xe2x80x2-biphenyl-2-carboxylate with tribromoborane in a second solvent to provide 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one;
treating 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one with a second transition metal catalyst under a hydrogen atmosphere at a pressure of about 20 to about 60 psi, preferably about 40 psi, in a third solvent, preferably N-methylpyrrolidin-2-one (NMP) at a concentration of about 0.5M to about 1.0M, preferably 0.7M, to provide 8-amino-1-hydroxy-6H-benzo[c]chromen-6-one in NMP;
treating 8-amino-1-hydroxy-6H-benzo[c]chromen-6-one in NMP with acetone and iodine and heating the reaction mixture to a temperature of about 95xc2x0 C. to about 115xc2x0 C., preferably about 105xc2x0 C., for about 60 to about 90 hours, preferably 72 hours, allowing the reaction mixture to cool to ambient temperature, filtering, concentrating and then adding ethyl acetate, washing the ethyl acetate solution with 10% sodium thiosulfate, water and then filtering the organics through a pad of celite, adding charcoal to the filtrate and heating the filtrate to reflux for 1 hour, passing the filtrate through a silica gel pad using ethyl acetate, concentrating the filtrate to provide a residue, diluting and reconcentrating the residue about 3 times, drying the residue under reduced pressure, adding acetone and 12M HCl to provide 10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one hydrochloride;
treating 10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one hydrochloride with a base and a methylating reagent in a fourth solvent to provide 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one;
treating 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one with a reducing agent in a fifth solvent to provide 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol;
isolating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol;
treating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol with allyltrimethylsilane and a Lewis acid to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
Isolating 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
resolving 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolinem to provide (5S) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline and (5R) 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline.
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term xe2x80x9cacidxe2x80x9d as used herein, means an organic or inorganic acid. Representative examples of organic acid include, but are not limited to oxalic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid and p-tolouenesulfonic acid. Representative examples of inorganic acid include, but are not limited to, hydrochloric acid (HCl) and hydrobromic acid (HBr). A preferred acid is HCl. A most preferred acid is 12M HCl.
The term xe2x80x9calkylxe2x80x9d as used herein, means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
The term xe2x80x9cbasexe2x80x9d as used herein, means any molecular moiety that can remove the hydrogen from an OH group that is attached to an unsubstituted or substituted phenyl group. Representative examples of base include, but are not limited to, alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide; hydrides such as sodium hydride, potassium hydride and lithium hydride; amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide. A preferred base is potassium tert-butoxide.
The term xe2x80x9cLewis acidxe2x80x9d as used herein, means a chemical species, other than a proton, that has a vacant orbital or accepts an electron pair. It is to be understood that Lewis acids can be purchased or prepared as complexes including but not limited to, etherates, hydrates, and thioetherates. Representative examples of Lewis acid include, but are not limited to, aluminum chloride, bismuth(III) chloride, boron trifluoride, iron(II) chloride, iron(III) chloride, magnesium bromide, magnesium chloride, magnesium trifluoromethanesulfonate, manganese(II) chloride, zinc bromide, zinc chloride, zirconium(IV) chloride, and the like.
The term xe2x80x9cmethylating reagentxe2x80x9d as used herein, means a reagent that provides an electrophilic source of a methyl group (CH3). Representative examples of a methylating reagent include, but are not limited to, iodomethane, bromomethane, chloromethane, dimethylsulfate and methyl fluorosulfonate. A preferred methylating reagent is dimethylsulfate.
The term xe2x80x9corganolithium reagentxe2x80x9d as used herein, means an alkyl group, as defined herein, wherein one hydrogen is removed to form a carbanion and the counter cation is lithium. Representative examples of organolithium reagent include, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium and methyllithium. A preferred organolithium reagent is n-butyllithium.
The term xe2x80x9creducing agentxe2x80x9d as used herein, means a hydride source that can reduce a lactone to a lactol. Representative examples of reducing agent include, but are not limited to, diisobutylaluminum hydride (DIBAL), lithium aluminum hydride (LAH) and sodium borohydride. A preferred reducing agent is diisobutylaluminum hydride.
The term xe2x80x9cfirst solventxe2x80x9d as used herein, means any organic solvent that will allow the reaction in step (a), the reaction in step (b) and the reaction in step (c) to proceed to completion or substantially to completion. A preferred first solvent is tetrahydrofuran.
The term xe2x80x9csecond solventxe2x80x9d as used herein, means any organic solvent that will allow the reaction in step (e) to proceed to completion or substantially to completion. A preferred second solvent is methylene chloride.
The term xe2x80x9cthird solventxe2x80x9d as used herein, means N-methylpyrrolidin-2-one.
The term xe2x80x9cfourth solventxe2x80x9d as used herein, means any organic solvent that will allow the reaction in step (1) to proceed to completion or substantially to completion. A preferred fourth solvent is tetrahydrofuran.
The term xe2x80x9cfifth solventxe2x80x9d as used herein, means any organic solvent that will allow the reaction in step (n) to proceed to completion or substantially to completion. A preferred fifth solvent is methylene chloride.
The term xe2x80x9cfirst transition metal catalystxe2x80x9d as used herein, means any transition metal catalyst that will allow the reaction in step (c) to proceed to completion or substantially to completion. A preferred first transition metal catalyst is dichloro-bis(triphenylphosphine)palladium(II).
The term xe2x80x9csecond transition metal catalystxe2x80x9d as used herein, means any transition metal catalyst that will allow the reaction in step (g) to proceed to completion or substantially to completion. A preferred second transition metal catalyst is 5% palladium on alumina.
The term xe2x80x9ctrialkylsilylalkenylxe2x80x9d as used herein, refers to a (RA)(RB)RCSiRD group wherein RA, RB and RC are alkyl and RD is alkenyl. Representative examples of trialkylsilylalkenyl include, but are no limited to allyl(trimethyl)silane, but-2-enyl(trimethyl)silane and but-3-enyl(trimethyl)silane.
The term xe2x80x9ctrialkylsilylalkynylxe2x80x9d as used herein, refers to a (RE)(RF)RGSiRH group wherein RE, RF and RG are alkyl and RH is alkynyl. Representative examples of trialkylsilylalkynyl include, but are no limited to trimethyl(prop-2-ynyl)silane, but-2-ynyl(trimethyl)silane and but-3-ynyl(trimethyl)silane.
Synthetic Process
Abbreviations which have been used in the descriptions of the Schemes and the Examples are: t-Bu for tert-butyl; n-BuLi for n-butyllithium; DIBAL or DIBAL-H for diisobutylaluminum hydride; DMF for N,N-dimethylformamide; EtOAc for ethyl acetate; EtOH for ethanol; HPLC for high pressure liquid chromatography; i-PrO for isopropoxy; Me for CH3; MeOH for methanol; NMP for N-methylpyrrolidin-2-one; Pd for palladium; Ph for phenyl; THF for tetrahydrofuran; TLC for thin layer chromatography; and p-TsOH for paratoluenesulfonic acid. 
A nine-step route, previously reported in International Patent PublicationNumber WO 99/41256, that was used for the preparation of smaller quantities of 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline is described in Scheme 1. 1,3-Dimethoxy benzene (1) was first lithiated at xe2x88x9278xc2x0 C. in hexane and diethyl ether followed by transmetalation with triisopropylborate. Hydrolysis of the boron ester afforded the boronic acid (2) in 77% yield. The boronic acid and commercially available 2-bromo-5-nitrobenzoate were subjected to modified Suzuki coupling conditions to provide the biaryl ester (3) in 75% yield. The biaryl ester was treated with boron tribromide to yield benzocoumarin (4) in 84% yield. The benzocoumarin (4) was methylated with methyl iodide in the presence of cesium carbonate to provide (5). The nitro functionality was reduced to the amino functionality by hydrogenolysis over palladium on carbon in 1,4-dioxane to produce the aniline derivative (6). The aniline derivative (6) was subjected to a modified Skraup reaction with acetone in the presence of iodine at 105xc2x0 C. for 72 hours to produce the 1,2-dihydro-2,2,4-trimethylquinoline (7) in 47% yield. A similar synthesis of 1,2-dihydro-2,2,4-trimethylquinoline (7) has been previously reported in J. Med. Chem., 41 (1998) 303-310. 1,2-Dihydro-2,2,4-trimethylquinoline (7) was reduced to the lactol (8) with DIBAL followed by methylation with methanol in the presence of p-TsOH to afford the methyl acetal (9) in 75% yield. The methyl acetal (9) was allylated with allyltrimethylsilane in the presence of boron trifluoride etherate to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline in 80% yield. The overall yield for the nine-step process described in Scheme 1 was 13%. 
A compound of formula (1), wherein R1 is H (R1 can be OCH3) and Y is H (Y can be Br or I), was lithiated with n-BuLi at 0xc2x0 C. in THF followed by transmetalation with ZnCl2 to generate the organozinc derivative. The organozinc derivative was reacted directly with a compound of formula (2), wherein X is Br (X can be I or xe2x80x94OSO2CF3), in the presence of a palladium catalyst such as dichloro-bis(triphenylphosphine)palladium at 45xc2x0 C. to provide the desired biaryl compound (3), wherein R1 is H, in essentially quantitative yield. The reaction went to completion within two hours and the product precipitated out of the reaction mixture which simplified the isolation and purification to a filtration to provide (3), wherein R1 is H, in high yield (85-90%) and high purity (99%). This procedure increased the reaction yield, improved the throughput and shortened the processing time three fold for the synthesis of the biaryl compound (3), wherein R1 is H. The preparation of the biaryl compound (3), wherein R1 is H, used in Scheme 1 was a two-step process with an overall yield of 58%. The formation of the boronic acid (2), in Scheme 1, required cryogenic reaction conditions and the Suzuki coupling reaction required a long reaction time (24 hours) at high temperature (100xc2x0 C.) with an excess of cesium carbonate in DMF. In addition, the extractive work-up procedure was very tedious due to a dark colored emulsion which resulted in a very difficult layer separation. Purification of the biaryl product (3), wherein R1 is H, was difficult as isolation of (3), wherein R1 is H, involved repeated washings.
The nitrocoumarin (4), wherein R1 is H, was hydrogenated to the aminocoumarin (11), wherein R1 is H, using 5% palladium on alumina at 60xc2x0 C. and 40-60 psi in NMP. Using NMP as solvent allowed the reaction concentration to be increased tenfold while reducing the reaction time from 40 hours to less than 2 hours. The reaction mixture was filtered and the filtrate used directly in the next step. The throughput was improved by tenfold and the next step (modified Skraup reaction) could be carried out at double the concentration. In the nine-step procedure described in Scheme 1, the hydrogenation used large volumes of 1,4-dioxane due to the poor solubility of the nitrocoumarin in 1,4-dioxane resulting in longer reaction times (over 40 hours). Also an impractical hot filtration of the palladium catalyst was necessary to avoid precipitation of the aminocoumarin (6) out of the solution.
The filtrate containing aminocoumarin (11), wherein R1 is H, was subjected to modified Skraup conditions and an improved isolation and purification procedure was developed involving an extractive workup procedure. Taking advantage of the solubility differences between the desired product (12), wherein R1 is H, and the by-products, a majority of the by-products were removed with a liquid-liquid extraction (EtOAc/heptane-H2O) and filtration. The purity of the crude product was increased from about 10% potency to more than 75% potency and was further improved to 90% by making a HCl salt. The product (12), wherein R1 is H, can be used directly in the next methylation step without further purification. Isolation and purification of the product of the modified Skraup reaction in Scheme 1 required column chromatography that used large volumes of solvent. One gram of crude product required over one liter of solvent for purification rendering the isolation of large quantities of compound (7) from Scheme 1 as impractical.
The modified Skraup product (12), wherein R1 is H, was then methylated to provide compound (7), wherein R1 is H, as described in Scheme 2. Reordering the sequence of reactions from the order described in Scheme 1 allowed the lower purity modified Skraup product (12), wherein R1 is H, to be methylated resulting in compound (7), wherein R1 is H, which could now be purified by crystallization instead of column chromatography. The crude methylation product with a potency of less than 70% was purified easily by crystallization with EtOAc/heptane to greater than 95% potency.
Compound (7), wherein R1 is H, was treated with DIBAL to provide lactol (8), wherein R1 is H. Lactol (8), wherein R1 is H, can be purified by crystallization from EtOAc/heptane and then can be directly allylated in excellent yield to provide the final product (10), wherein R1 is H. The allylation reaction was carried out at 0xc2x0 C. under threefold concentrated conditions using two equivalents of allyl(trimethyl)silane instead of four. As a result, formation of the methyl acetal (9) from Scheme 1 and the column chromatography purification steps used to isolate acetal (9) were removed. Also, the column chromatography purification step for the final product (10) was eliminated as well. The final product (10) was crystallized using polar solvents, such as EtOH or iPrOH. Thus, the high purity ( greater than 99%) final product was obtained in 95% isolated yield using a filtration procedure.
The present invention is directed to an efficient process for the synthesis of 5-(substituted)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines, in particular 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline, with an overall yield of 24% and elimination of all column chromatography purification steps. The synthesis of the biaryl compound (3), wherein R1 is H, was accomplished in a high yield one-pot procedure. The throughput for the hydrogenation of the nitro coumarin (4), wherein R1 is H, to the aminocoumarin (11), wherein R1 is H, was increased tenfold with use of NMP as the solvent. The isolation of the aminocoumarin (11), wherein R1 is H, was eliminated addressing the issue of the stability of the aminocoumarin intermediate and also enabled the reaction concentration for the modified Skraup reaction to be doubled. The labor-intensive, tedious column chromatography purification step in the modified Skraup reaction was replaced with an efficient extractive work-up procedure. The methylation step was reordered so that the intermediate (7), wherein R1 is H, could be purified by crystallization. A direct allylation of lactol (8), wherein R1 is H, with allyltrimethylsilane was achieved allowing the elimination of methyl acetal formation and its column chromatography purification step as well as increasing the reaction concentration threefold. Finally, a crystalline solid was obtained for 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (10) making the isolation/purification of (10), wherein R1 is H, practical.
5-(Allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline was resolved into its individual (5S) and (5R) enantiomers using the procedure described in Example 8. Resolution techniques well known in the art such as fractional crystallization and the use of chiral auxiliaries can also be used for isolation of the (5S) and (5R) enantiomers.
It is to be understood that the process in Scheme 2 can be used to prepare 9,10-dihydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one.
The present invention is now more particularly described by the following Examples which are not intended to limit the scope the present invention. The present invention covers all alternatives, modifications and equivalents included in the appended claims. Thus, the following Examples illustrate a preferred practice of the invention, it being understood that the Examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.
The NMR spectra were recorded on a Varain Unity 500 MHz instrument at 500.5 MHz for 1H and 125.9 MHz for 13C. The electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) mass spectra were obtained using a Hewlett Packard 1100, LC-MS, HPLC-mass spectrometer and fast atom bombardment (FAB) mass spectra were obtained using a JEOL SX102A spectrometer. Commercial grade anhydrous solvents and reagents were used without further purification. All reactions were monitored by HPLC (using Zorbax SB-C8, 4.6 mmxc3x9725 cm column) with purities being determined by peak area % at 210 and 228 nm.